Deuterated Alpha5 subunit-selective negative allosteric modulators of gamma-aminobutyric acid type A receptors as fast acting treatment for depression and mood disorders
Inventors
Thompson, Scott • Van Dyke, Adam • Thomas, Craig • Morris, Patrick
Assignees
University of Maryland Baltimore • US Department of Health and Human Services
Publication Number
US-11459320-B2
Publication Date
2022-10-04
Expiration Date
2038-08-28
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Abstract
The present invention relates to novel alpha5 subunit-selective negative allosteric modulators of GABAA receptors that have been deuterated to improve their medicinal properties by prolonging their half-lives, rendering them useful as fast-acting pharmaceutical treatments for depression related disorders.
Core Innovation
The invention relates to novel deuterated alpha5 subunit-selective negative allosteric modulators (NAMs) of gamma-aminobutyric acid type A (GABAA) receptors. These compounds have improved medicinal properties due to deuteration at specific sites, which prolongs their half-lives in the human body. The extended half-life enables their use as fast-acting pharmaceutical treatments for depression and mood disorders.
The problem solved by the invention is the limitations of current antidepressant therapies, which include prolonged onset of efficacy, often requiring 6-8 weeks, and limited effectiveness in about 50% of patients. Existing alpha5 subunit-selective GABAA NAMs suffer from short biological half-lives due to rapid metabolic hydrolysis by liver enzymes, reducing bioavailability and therapeutic efficacy. There are no FDA-approved fast-acting antidepressants without significant side effects like abuse liability or psychosis-like responses. The invention addresses the need for new drugs with rapid antidepressant action and improved pharmacokinetic profiles.
The invention provides compositions and methods for treating depression-related and other psychiatric conditions using deuterated alpha5-subunit selective negative allosteric modulators of GABAA receptors. Deuteration is performed at metabolic hydrolysis sites to slow compound breakdown in the liver, thereby increasing bioavailability, prolonging half-life, enabling less frequent dosing, and enhancing clinical utility as fast-acting antidepressants. Preferred compounds include deuterated derivatives of known alpha5 selective NAMs such as RG-1662 (NCGC-43). The invention also encompasses synthetic methods for producing these deuterated compounds and methods of administration to human subjects in need.
Claims Coverage
The patent includes six claims, of which claims 1, 3, and 6 are independent. The main inventive features relate to the chemical structure of deuterated GABAA5-NAM compounds, methods of synthesis, and improved pharmacokinetic properties.
Deuterated GABAA5-NAM compound according to Formula I
The invention of a deuterated GABAA alpha5 subunit-selective negative allosteric modulator compound defined by Formula I, where at least one hydrogen atom in specific positions is replaced by deuterium, enhancing half-life and medicinal properties.
Deuterated RG-1662 compound
A specific deuterated GABAA5-NAM compound variant, derived from (1,1-dioxidothiomorpholino)(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridin-3-yl)methanone (RG-1662), wherein one or more hydrogens are substituted by deuterium to improve pharmacokinetic stability.
Deuterated GABAA5-NAM compound according to Formula II
A particular structural embodiment of the deuterated GABAA5-NAM compound having the substitution pattern specified in Formula II, further illustrating the chemical nature of the invention.
Method of synthesizing deuterated Basmisanil-related compound
A synthetic method involving (a) treatment of (3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methanol with base and a deuterium donor, (b) reaction with 6-chloronicotinonitrile or methyl 6-chloronicotinate, (c) hydrolysis to carboxylic acid, and (d) amide coupling with thiomorpholine 1,1-dioxide or salt, yielding a deuterated Basmisanil derivative.
Use of D2O or CD3OD as deuterium donor
The selection of deuterium donors D2O or CD3OD in the synthetic process for incorporating deuterium atoms at specific molecular positions of the GABAA5-NAM compounds.
Deuterated GABAA5-NAM compound with longer biological half-life
The deuterated GABAA5-NAM compounds exhibit an increased biological half-life when administered to mammals compared to the corresponding non-deuterated compounds, providing enhanced therapeutic duration and bioavailability.
The claims collectively define deuterated alpha5 subunit-selective negative allosteric modulators of GABA receptors with specified chemical structures and methods of synthesis, highlighting the improved biological half-life and pharmacological utility conferred by targeted deuteration.
Stated Advantages
Prolonged half-life in mammals increases bioavailability of the compounds, reducing dosing frequency.
Enhanced therapeutic efficacy of alpha5-selective negative allosteric modulators as fast-acting antidepressants.
Reduced side effects and improved patient compliance due to decreased need for frequent dosing.
Deuteration provides stable, non-toxic modifications that preserve pharmacological activity while improving metabolic stability.
Documented Applications
Treatment of depression-related disorders including major depressive disorder, dysthymia, suicidality, bipolar depression, psychotic depression, atypical depression, seasonal affective disorder, and postpartum depression.
Treatment or amelioration of anxiety-related disorders, attention-related disorders, psychosis-related disorders, personality disorders, eating disorders, cognitive impairment including traumatic brain injury-related impairment.
Management of neuropathic pain, chronic muscle or bone pain, diabetic nerve injury complications, generalized muscle weakness, recurring sleep episodes, migraine, addiction, alcoholism, and substance use disorders.
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